Mutations in the presenilin proteins cause the majority of familial Alzheimer's disease (FAD). In 1998 we identified and initiated the characterization of calsenilin, a neuronal calcium binding protein that interacts with the C-terminal domain of presenilin 1 and presenilin 2. Because calsenilin interacts with both of the presenilins, the elucidation of its normal biological role should provide information about pathways shared by the two proteins, such as those involved in the AD-associated increases in ABeta. Since our original identification, other investigators have found that calsenilin can also interact with and modulate the activity of A-type K+ channels and act as a transcriptional repressor for a number of genes, including dynorphin. In this competing renewal we will continue to focus on calsenilin and on the regulation of its interaction with the presenilins. In addition, we address the newly identified functions of calsenilin (as a modulator of A-type K+ channel activity and transcriptional repression) with the long-term purpose of understanding any potential relevance to the neurodegeneration associated with AD. To accomplish this we propose a series of aims designed to learn more about the regulation of the interaction of calsenilin with its binding partners and to identify proteins that interact with the unique N-terminal domain of the protein. We also propose to assess the processes responsible for the regulation of the translocation of calsenilin from the cytoplasm, where it is presumably interacting with the presenilins and the K+ channel, to the nucleus, where it appears to bind to DNA and have a role as a calcium-regulated transcriptional repressor. Finally, we will utilize a recently generated calsenilin knockout mouse to address the role that calsenilin plays in presenilin and K+ channel trafficking and function. The experiments described in this application should supply fundamental but critical information about the basic cell biology of calsenilin and its interaction with the presenilins, the Kv channel and DNA regulatory element that control expression of dynorphin and c-fos. These studies will be a valuable asset for understanding not only the biology of calsenilin, but also of its interactors, and ultimately this information should be useful in understanding presenilin and K+ channel associated Ca2+-signaling pathways in the brain.